The impact of tumor stromal architecture on therapy response and clinical progression

Abstract

Abstract — Advances in molecular oncology research culminated in the development of targeted therapies that act on defined molecular targets either on tumor cells directly (such as inhibitors of oncogenic kinases), or indirectly by targeting the tumor microenvironment (such as anti-angiogenesis drugs). These therapies can induce strong clinical responses, when properly matched to patients. Unfortunately, most targeted therapies ultimately fail as tumors evolve resistance. Tumors consist not only of neoplastic cells, but also of stroma, whereby “stroma” is the umbrella term for non-tumor cells and extracellular matrix (ECM) within the tumor microenvironment, possibly excluding immune cells 1 . We know that tumor stroma is an important player in the development of resistance. We also know that stromal architecture is spatially complex, differs from patient to patient and changes with therapy. However, to this date we do not understand the link between spatial and temporal changes in stromal architecture and response of tumors to therapy, in space and time. In this project we sought to address this gap of knowledge using a combination of mathematical and statistical modeling, experimental in vivo studies, and analysis of clinical samples in therapies that target tumor cells directly (in lung and breast cancers) and indirectly (in kidney cancer). This knowledge will inform therapy choices and offer new angles for therapeutic interventions. Our main question is: how does spatial architecture of stroma impact the emergence or evolution of resistance to targeted therapies, and how can we use this knowledge clinically?